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Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase.

Authors
  • Flinspach, Mack L
  • Li, Huiying
  • Jamal, Joumana
  • Yang, Weiping
  • Huang, Hui
  • Hah, Jung-Mi
  • Gómez-Vidal, José Antonio
  • Litzinger, Elizabeth A
  • Silverman, Richard B
  • Poulos, Thomas L
Type
Published Article
Journal
Nature Structural & Molecular Biology
Publisher
Springer Nature
Publication Date
Jan 01, 2004
Volume
11
Issue
1
Pages
54–59
Identifiers
PMID: 14718923
Source
Medline
License
Unknown

Abstract

Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-N(omega)-nitroarginine-containing dipeptide inhibitors.

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